open access

Vol 52, No 1 (2021)
Review article
Submitted: 2021-02-07
Accepted: 2021-02-07
Get Citation

Clinical implications of cytogenetic and molecular aberrations in multiple myeloma

Sarah Goldman-Mazur, David H. Vesole, Artur Jurczyszyn
DOI: 10.5603/AHP.2021.0004
·
Acta Haematol Pol 2021;52(1):18-28.

open access

Vol 52, No 1 (2021)
REVIEW ARTICLE
Submitted: 2021-02-07
Accepted: 2021-02-07

Abstract

Multiple myeloma (MM) is an incurable haematological malignancy affecting approximately 7:100,000 people. Monoclonal gammopathy of undetermined significance (MGUS) and ‘smouldering’ MM precede symptomatic MM. Cytogenetics in MM is the most powerful prognostication tool incorporated into different classifications, including the Revised International Staging System (R-ISS) and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART). Methods commonly used to test for cytogenetic aberrations include conventional karyotyping and fluorescence in situ hybridisation (FISH), although the difficulty of obtaining metaphases in plasma cells results in low yields. Therefore, new genomic tools are essential to explore the complex landscape of genetic alterations in MM. These include next generation sequencing, a highly sensitive method to monitor minimal residual disease. The serial evolution of MGUS to MM is accompanied by a range of heterogenous genetic abnormalities, divided into primary (involving mostly chromosome 14 translocations and trisomies) and secondary genetic aberration events (involving mostly 17p, 1p, 13q deletions, 1q gain, or MYC translocations). Based on the primary genetic aberration results, strong prognostic features of MM have been identified with distinct clinical characteristics. High risk aberrations include 17p deletion, t(4;14), t(14;16), t(14;20) and chromosome 1 abnormalities. The incorporation of novel drugs and maintenance strategies in conjunction with autologous stem cell transplantation partially overcome the adverse effect of some of these genetic aberrations. Nonetheless, survival remains worse in this group compared to standard risk patients. Clinical decisions regarding treatment should be based on the cytogenetic results. The establishment of individualised and mutation-targeted therapies are of the greatest importance in future studies.

Abstract

Multiple myeloma (MM) is an incurable haematological malignancy affecting approximately 7:100,000 people. Monoclonal gammopathy of undetermined significance (MGUS) and ‘smouldering’ MM precede symptomatic MM. Cytogenetics in MM is the most powerful prognostication tool incorporated into different classifications, including the Revised International Staging System (R-ISS) and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART). Methods commonly used to test for cytogenetic aberrations include conventional karyotyping and fluorescence in situ hybridisation (FISH), although the difficulty of obtaining metaphases in plasma cells results in low yields. Therefore, new genomic tools are essential to explore the complex landscape of genetic alterations in MM. These include next generation sequencing, a highly sensitive method to monitor minimal residual disease. The serial evolution of MGUS to MM is accompanied by a range of heterogenous genetic abnormalities, divided into primary (involving mostly chromosome 14 translocations and trisomies) and secondary genetic aberration events (involving mostly 17p, 1p, 13q deletions, 1q gain, or MYC translocations). Based on the primary genetic aberration results, strong prognostic features of MM have been identified with distinct clinical characteristics. High risk aberrations include 17p deletion, t(4;14), t(14;16), t(14;20) and chromosome 1 abnormalities. The incorporation of novel drugs and maintenance strategies in conjunction with autologous stem cell transplantation partially overcome the adverse effect of some of these genetic aberrations. Nonetheless, survival remains worse in this group compared to standard risk patients. Clinical decisions regarding treatment should be based on the cytogenetic results. The establishment of individualised and mutation-targeted therapies are of the greatest importance in future studies.

Get Citation

Keywords

myeloma, cytogenetics, prognosis, high risk, genomics, aberration

About this article
Title

Clinical implications of cytogenetic and molecular aberrations in multiple myeloma

Journal

Acta Haematologica Polonica

Issue

Vol 52, No 1 (2021)

Article type

Review article

Pages

18-28

DOI

10.5603/AHP.2021.0004

Bibliographic record

Acta Haematol Pol 2021;52(1):18-28.

Keywords

myeloma
cytogenetics
prognosis
high risk
genomics
aberration

Authors

Sarah Goldman-Mazur
David H. Vesole
Artur Jurczyszyn

References (107)
  1. Kyle RA, Therneau T, Rajkumar S, et al. Incidence of multiple myeloma in Olmsted County, Minnesota. Cancer. 2004; 101(11): 2667–2674.
  2. Howell DA, Smith AG, Jack A, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011; 105(11): 1684–1692.
  3. Tsang M, Le M, Ghazawi FM, et al. Multiple myeloma epidemiology and patient geographic distribution in Canada: A population study. Cancer. 2019; 125(14): 2435–2444.
  4. Therneau TM, Kyle RA, Melton LJ, et al. Incidence of monoclonal gammopathy of undetermined significance and estimation of duration before first clinical recognition. Mayo Clin Proc. 2012; 87(11): 1071–1079.
  5. Kumar SK, Rajkumar SV. The multiple myelomas — current concepts in cytogenetic classification and therapy. Nat Rev Clin Oncol. 2018; 15(7): 409–421.
  6. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003; 78(1): 21–33.
  7. Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020; 95(5): 548–567.
  8. Robiou du Pont S, Cleynen A, Fontan C, et al. Genomics of multiple myeloma. J Clin Oncol. 2017; 35(9): 963–967.
  9. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017; 389(10068): 519–527.
  10. Hanbali A, Hassanein M, Rasheed W, et al. The evolution of prognostic factors in multiple myeloma. Adv Hematol. 2017; 2017: 4812637.
  11. Corre J, Munshi N, Avet-Loiseau H. Genetics of multiple myeloma: another heterogeneity level? Blood. 2015; 125(12): 1870–1876.
  12. Corre J, Cleynen A, Robiou du Pont S, et al. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia. 2018; 32(12): 2636–2647.
  13. Merz M, Hielscher T, Schult D, et al. Cytogenetic subclone formation and evolution in progressive smoldering multiple myeloma. Leukemia. 2020; 34(4): 1192–1196.
  14. Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015; 5: e365.
  15. Bergsagel PL, Nardini E, Brents L, et al. Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA. 1996; 93(24): 13931–13936.
  16. Rajkumar SV. Prevention of progression in monoclonal gammopathy of undetermined significance. Clin Cancer Res. 2009; 15(18): 5606–5608.
  17. Rajkumar SV, Fonseca R, Dewald GW, et al. Cytogenetic abnormalities correlate with the plasma cell labeling index and extent of bone marrow involvement in myeloma. Cancer Genet Cytogenet. 1999; 113(1): 73–77.
  18. Avet-Loiseau H, Daviet A, Brigaudeau C, et al. Cytogenetic, interphase, and multicolor fluorescence in situ hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du Myélome and the Groupe Français de Cytogénétique Hématologique. Blood. 2001; 97(3): 822–825.
  19. Soekojo CY, Wang GM, Chen Y, et al. Role of conventional karyotyping in multiple myeloma in the era of modern treatment and FISH analysis. Clin Lymphoma Myeloma Leuk. 2019; 19(8): e470–e477.
  20. Kapoor P, Fonseca R, Rajkumar SV, et al. Evidence for cytogenetic and fluorescence in situ hybridization risk stratification of newly diagnosed multiple myeloma in the era of novel therapie. Mayo Clin Proc. 2010; 85(6): 532–537.
  21. Tian E. Fluorescence in situ hybridization (FISH) in multiple myeloma. Methods Mol Biol. 2018; 1792: 55–69.
  22. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004; 64(4): 1546–1558.
  23. Ross FM, Avet-Loiseau H, Ameye G, et al. European Myeloma Network. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012; 97(8): 1272–1277.
  24. Hartmann L, Biggerstaff JS, Chapman DB, et al. Detection of genomic abnormalities in multiple myeloma: the application of FISH analysis in combination with various plasma cell enrichment techniques. Am J Clin Pathol. 2011; 136(5): 712–720.
  25. Saxe D, Seo EJ, Bergeron MB, et al. Recent advances in cytogenetic characterization of multiple myeloma. Int J Lab Hematol. 2019; 41(1): 5–14.
  26. An G, Li Z, Tai YT, et al. The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res. 2015; 21(9): 2148–2156.
  27. Bolli N, Biancon G, Moarii M, et al. Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups. Leukemia. 2018; 32(12): 2604–2616.
  28. Bolli N, Genuardi E, Ziccheddu B, et al. Next-generation sequencing for clinical management of multiple myeloma: ready for prime time? Front Oncol. 2020; 10: 189.
  29. Hoang ML, Chen CH, Sidorenko VS, et al. Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing. Sci Transl Med. 2013; 5(197): 197ra102.
  30. Samur MK, Aktas Samur A, Fulciniti M, et al. Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group. J Clin Oncol. 2020; 38(27): 3107–3118.
  31. Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet. 2011; 204(1): 3–12.
  32. Kuiper R, Broyl A, de Knegt Y, et al. A gene expression signature for high-risk multiple myeloma. Leukemia. 2012; 26(11): 2406–2413.
  33. Kuiper R, van Duin M, van Vliet MH, et al. Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System. Blood. 2015; 126(17): 1996–2004.
  34. Shaughnessy JD, Zhan F, Burington BE, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007; 109(6): 2276–2284.
  35. Smetana J, Frohlich J, Zaoralova R, et al. Genome-wide screening of cytogenetic abnormalities in multiple myeloma patients using array-CGH technique: a Czech multicenter experience. Biomed Res Int. 2014; 2014: 209670.
  36. Avet-Loiseau H, Li C, Magrangeas F, et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol. 2009; 27(27): 4585–4590.
  37. Kumar S, Fonseca R, Ketterling RP, et al. Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood. 2012; 119(9): 2100–2105.
  38. Chretien ML, Corre J, Lauwers-Cances V, et al. Understanding the role of hyperdiploidy in myeloma prognosis: which trisomies really matter? Blood. 2015; 126(25): 2713–2719.
  39. Vu T, Gonsalves W, Kumar S, et al. Characteristics of exceptional responders to lenalidomide-based therapy in multiple myeloma. Blood Cancer J. 2015; 5: e363.
  40. Pawlyn C, Melchor L, Murison A, et al. Coexistent hyperdiploidy does not abrogate poor prognosis in myeloma with adverse cytogenetics and may precede IGH translocations. Blood. 2015; 125(5): 831–840.
  41. Carballo-Zarate AA, Medeiros LJ, Fang L, et al. Additional-structural-chromosomal aberrations are associated with inferior clinical outcome in patients with hyperdiploid multiple myeloma: a single-institution experience. Mod Pathol. 2017; 30(6): 843–853.
  42. Van Wier S, Braggio E, Baker A, et al. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma. Haematologica. 2013; 98(10): 1586–1592.
  43. Smadja NV, Bastard C, Brigaudeau C, et al. Groupe Français de Cytogénétique Hématologique. Hypodiploidy is a major prognostic factor in multiple myeloma. Blood. 2001; 98(7): 2229–2238.
  44. Walker BA, Wardell CP, Johnson DC, et al. Characterization of IGH locus breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pregerminal center B cells. Blood. 2013; 121(17): 3413–3419.
  45. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012; 12(5): 335–348.
  46. Pratt G, Fenton JA, Proffitt JA, et al. True spectrum of 14q32 translocations in multiple myeloma. Br J Haematol. 1998; 103(4): 1209–1210.
  47. Fonseca R, Debes-Marun CS, Picken EB, et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood. 2003; 102(7): 2562–2567.
  48. Avet-Loiseau H, Hulin C, Campion L, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007; 109(8): 3489–3495.
  49. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003; 101(11): 4569–4575.
  50. Garand R, Avet-Loiseau H, Accard F, et al. t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia. 2003; 17(10): 2032–2035.
  51. Greenberg AJ, Rajkumar SV, Therneau TM, et al. Relationship between initial clinical presentation and the molecular cytogenetic classification of myeloma. Leukemia. 2014; 28(2): 398–403.
  52. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010; 28(30): 4630–4634.
  53. El-Ghammaz AMS, Abdelwahed E. Bortezomib-based induction improves progression-free survival of myeloma patients harboring 17p deletion and/or t(4;14) and overcomes their adverse prognosis. Ann Hematol. 2016; 95(8): 1315–1321.
  54. Jackson GH, Davies FE, Pawlyn C, et al. UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019; 20(1): 57–73.
  55. Yan X, Xu XuS, Weisel KC, et al. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. Haematologica. 2015; 100(10): 1334–1339.
  56. Walker BA, Wardell CP, Murison A, et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat Commun. 2015; 6: 6997.
  57. Fonseca R, Blood EA, Oken MM, et al. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood. 2002; 99(10): 3735–3741.
  58. Kobayashi A, Misumida N, Aoi S, et al. Prevalence and clinical implication of Wellens' sign in patients with non-ST-segment elevation myocardial infarction. Cardiol Res. 2019; 10(3): 135–141.
  59. Royer B, Minvielle S, Diouf M, et al. Bortezomib, doxorubicin, cyclophosphamide, dexamethasone induction followed by stem cell transplantation for primary plasma cell leukemia: a prospective phase II study of the Intergroupe Francophone du Myélome. J Clin Oncol. 2016; 34(18): 2125–2132.
  60. Jurczyszyn A, Radocha J, Davila J, et al. Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients. Br J Haematol. 2018; 180(6): 831–839.
  61. Sasaki K, Lu G, Saliba RM, et al. Impact of t(11;14)(q13;q32) on the outcome of autologous hematopoietic cell transplantation in multiple myeloma. Biol Blood Marrow Transplant. 2013; 19(8): 1227–1232.
  62. Lakshman A, Alhaj Moustafa M, Rajkumar SV, et al. Natural history of t(11;14) multiple myeloma. Leukemia. 2018; 32(1): 131–138.
  63. Gasparetto C, Abonour R, Jagannath S, et al. Impact of t(11;14) on outcomes in African American (AA) and non-AA (NAA) patients (Pts) with newly diagnosed multiple myeloma (NDMM): Connect MM registry. J Clin Oncol. 2017; 35(15_Suppl): 8023.
  64. Kazandjian D, Hill E, Hultcrantz M, et al. Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients. Blood Cancer J. 2019; 9(2): 15.
  65. Robillard N, Avet-Loiseau H, Garand R, et al. CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood. 2003; 102(3): 1070–1071.
  66. Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015; 33(26): 2863–2869.
  67. Goldman‐Mazur S, Jurczyszyn A, Castillo J, et al. A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma. Am J Hematol. 2020; 95(5): 503–509.
  68. Abdallah N, Rajkumar SV, Greipp P, et al. Cytogenetic abnormalities in multiple myeloma: association with disease characteristics and treatment response. Blood Cancer J. 2020; 10(8): 82.
  69. Narita T, Inagaki A, Kobayashi T, et al. t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs. Blood Cancer J. 2015; 5: e285.
  70. Goldman-Mazur S, Jurczyszyn A, Castillo JJ, et al. Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients. Leuk Lymphoma. 2020; 61(8): 1885–1893.
  71. Mikhael JR, Dingli D, Roy V, et al. Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013; 88(4): 360–376.
  72. Weinhold N, Kirn D, Seckinger A, et al. Concomitant gain of 1q21 and MYC translocation define a poor prognostic subgroup of hyperdiploid multiple myeloma. Haematologica. 2016; 101(3): e116–e119.
  73. Dib A, Gabrea A, Glebov OK, et al. Characterization of MYC translocations in multiple myeloma cell lines. J Natl Cancer Inst Monogr. 2008(39): 25–31.
  74. Chesi M, Bergsagel PL. Advances in the pathogenesis and diagnosis of multiple myeloma. Int J Lab Hematol. 2015; 37(Suppl 1): 108–114.
  75. Abdallah N, Greipp P, Kapoor P, et al. Clinical characteristics and treatment outcomes of newly diagnosed multiple myeloma with chromosome 1q abnormalities. Blood Adv. 2020; 4(15): 3509–3519.
  76. Hanamura I, Stewart JP, Huang Y, et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood. 2006; 108(5): 1724–1732.
  77. Giri S, Huntington SF, Wang R, et al. Chromosome 1 abnormalities and survival of patients with multiple myeloma in the era of novel agents. Blood Adv. 2020; 4(10): 2245–2253.
  78. An G, Xu Y, Shi L, et al. Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value. Haematologica. 2014; 99(2): 353–359.
  79. Hebraud B, Leleu X, Lauwers-Cances V, et al. Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: the IFM experience on 1195 patients. Leukemia. 2014; 28(3): 675–679.
  80. Varma A, Sui D, Milton DR, et al. Outcome of multiple myeloma with chromosome 1q gain and 1p deletion after autologous hematopoietic stem cell transplantation: propensity score matched analysis. Biol Blood Marrow Transplant. 2020; 26(4): 665–671.
  81. Chiecchio L, Dagrada GP, Ibrahim AH, et al. UK Myeloma Forum. Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context. Haematologica. 2009; 94(12): 1708–1713.
  82. Chiecchio L, Protheroe RKM, Ibrahim AH, et al. Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia. 2006; 20(9): 1610–1617.
  83. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007; 21(1): 151–157.
  84. Tiedemann RE, Gonzalez-Paz N, Kyle RA, et al. Genetic aberrations and survival in plasma cell leukemia. Leukemia. 2008; 22(5): 1044–1052.
  85. Lakshman A, Painuly U, Rajkumar SV, et al. Natural history of multiple myeloma with de novo del(17p). Blood Cancer J. 2019; 9(3): 32.
  86. Thanendrarajan S, Tian E, Qu P, et al. The level of deletion 17p and bi-allelic inactivation of has a significant impact on clinical outcome in multiple myeloma. Haematologica. 2017; 102(9): e364–e367.
  87. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial. J Clin Oncol. 2019; 37(7): 589–597.
  88. Cavo M, Gay F, Beksac M, et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020; 7(6): e456–e468.
  89. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012; 30(24): 2946–2955.
  90. Leleu X, Karlin L, Macro M, et al. Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015; 125(9): 1411–1417.
  91. Pasca S, Tomuleasa C, Teodorescu P, et al. KRAS/NRAS/BRAF mutations as potential targets in multiple myeloma. Front Oncol. 2019; 9: 1137.
  92. Andrulis M, Lehners N, Capper D, et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013; 3(8): 862–869.
  93. Liu P, Leong T, Quam L, et al. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood. 1996; 88(7): 2699–2706.
  94. Mulligan G, Lichter D, Bacco ADi, et al. Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy. Blood. 2014; 123(5): 632–639.
  95. Boyd KD, Ross FM, Chiecchio L, et al. NCRI Haematology Oncology Studies Group. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012; 26(2): 349–355.
  96. Baysal M, Demirci U, Umit E, et al. Concepts of double hit and triple hit disease in multiple myeloma, entity and prognostic significance. Sci Rep. 2020; 10(1): 5991.
  97. Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009; 84(12): 1095–1110.
  98. Caers Jo, Garderet L, Kortüm KM, et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when. Haematologica. 2018; 103(11): 1772–1784.
  99. Kumar SK, Callander NS, Hillengass J, et al. et al.. NCCN guidelines insights: multiple meloma, version 1.2020. J Natl Compr Canc Netw. 2019; 17(10): 1154–1165.
  100. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12): 2210–2221.
  101. Giannopoulos KJK, Usnarska-Zubkiewicz L, Dytfeld D, et al. Recommendations of Polish Myeloma Group concerning diagnosis and therapy of multiple myeloma and other plasmacytic dyscrasias for 2018/2019. Acta Hematol Pol. 2018; 49(4): 157–206.
  102. Majithia N, Rajkumar SV, Lacy MQ, et al. Early relapse following initial therapy for multiple myeloma predicts poor outcomes in the era of novel agents. Leukemia. 2016; 30(11): 2208–2213.
  103. Kumar SK, Dispenzieri A, Fraser R, et al. Early relapse after autologous hematopoietic cell transplantation remains a poor prognostic factor in multiple myeloma but outcomes have improved over time. Leukemia. 2018; 32(4): 986–995.
  104. Romano A, Palumbo GA, Parrinello NL, et al. Minimal residual disease assessment within the bone marrow of multiple myeloma: a review of caveats, clinical significance and future perspectives. Front Oncol. 2019; 9: 699.
  105. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017; 130(8): 974–981.
  106. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014; 123(20): 3073–3079.
  107. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018; 132(23): 2456–2464.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
tel.:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: journals@viamedica.pl